This proposal aims to test the hypothesis that clock genes in the VTA and terminal regions of the mesolimbic DA system are responsible for circadian fluctuations in the motivation to self-administer cocaine. Cocaine users exhibit fluctuations in their motivation to take drug, with recreational use transitioning into binge abstinence cycles. Animal models of cocaine self-administration also show cycles in motivation to obtain cocaine relative to the time of day. Recently, clock genes have been shown to play an important role in modulating drug reinforcement. Here we propose two methods to examine the circadian influences on cocaine intake: fast-scan cyclic voltammetry (FSCV) to investigate rhythms in dopamine (DA) transporter activity and recombinant adeno-associated viruses (AAV) to allow disruption of clock gene functions in a regionally specific manner. Specifically, I will use FSCV to determine whether DA transporter (DAT) activity demonstrates a circadian rhythm. I will also generate recombinant AAV vectors that manipulate rat clock gene expression patterns and characterize the kinetic parameters that lead to alterations in expression. Finally, I will examine the effects of regionally specific clock gene knockdowns on cocaine self-administration. An understanding of how clock genes interact with cocaine reinforcement is important because an understanding of physiological processes which dampen interest in drugs could provide new therapeutic targets to treat addiction. Additionally, the cycles in motivation to take cocaine could reflect a disruption in circadian influences normally controlling the timing and duration of drug taking.